Erythromycins A through D, represented by formula (I),
______________________________________ ##STR2## (I) Erythromycin R.sup.a R.sup.b ______________________________________ A OH CH.sub.3 B H CH.sup.3 C OH H D H H ______________________________________
are well-known and potent antibacterial agents. Erythromycin A in particular is widely used to treat and prevent bacterial infection. As with other antibacterials, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
Examples of such analogs include (9R)-9,9-dihydro-9,11-di-O-thiocarbonylerythromycin A, reported by Hauske et al. in J. Org. Chem., 48:5138 (1983), and the 12,12'-anhydro-(9R)-hydroxy-9-deoxoerythromycin derivatives prepared therefrom according to Hauske in European Patent Application No. 303 471, published Feb. 15, 1989. These latter derivatives are characterized by the presence, in the final product or during synthesis, of C.sub.2 -C.sub.4 alkanoate esters at the 4" position, and preferably of a 4" acetate group. Such substituents appear to result in a reduction of antibacterial activity, however, as well as a limitation upon the range of possible substituents at other positions when the 4" alkanoate moiety is ultimately removed.
Other analogs of erythromycin include those in which the ketone at position 9 is substituted with an amine as in (9S)-9-amino-9-deoxoerythromycin A (erythromycylamine), described by Massey et al. in U.S. Pat. No. 3,652,537, issued Mar. 28, 1972. 9-N-substituted derivatives of these analogs have also been reported, as by Bonjoukliah et al. in European Patent Application No. 238 178, published Sep. 23, 1987, by Pariza et al. in European Patent 345 627, published Dec. 13, 1989, and by Maring et al. in 29th ICACC, Abstr. 1023-1025, 1989 (disclosing azacyclic derivatives). There has been no suggestion, however, of the further functionalization of 9-N-substituted derivatives by modification at C-12 and C-21.